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Inactivating CUX1 mutations promote tumorigenesis

2013; Nature Portfolio; Volume: 46; Issue: 1 Linguagem: Inglês

10.1038/ng.2846

1546-1718

Chi Chun Wong, Sancha Martin, Alistair G. Rust, Mamunur Rashid, Constantine Alifrangis, Ludmil B. Alexandrov, Jessamy Tiffen, Christina Kober, Anthony R. Green, Charles Massie, Jyoti Nangalia, Stella Lempidaki, Hartmut Döhner, Konstanze Döhner, Sarah J. Bray, Ultan McDermott, Elli Papaemmanuil, Peter J. Campbell, David J. Adams,

Chromatin Remodeling and Cancer

David Adams and colleagues identify inactivating mutations in CUX1 in diverse human cancers. They validate CUX1 as a tumor suppressor using mouse and Drosophila cancer models, and show that CUX1 deficiency activates phosphoinositide 3-kinase signaling through transcriptional downregulation of a PI3K inhibitor. A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ∼1–5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.